title: Proteome of ubiquitin/MVB pathway: possible involvement of iron-induced ubiquitylation of transferrin receptor in lysosomal degradation.
abstract: Ubiquitylation of membrane proteins triggers their endocytosis at the plasma membrane and subsequent lysosomal degradation through multivesicular bodies (MVBs). A dominant-negative mutant SKD1/Vps4B caused an accumulation of ubiquitylated membrane proteins in MVBs. We have identified 22 membrane proteins whose trafficking is potentially regulated by ubiquitylation. Nine of them, including transferrin receptor (TfR), are indeed ubiquitylated and/or accumulated in MVBs in the cells expressing mutant Vps4. While the recycling route and iron-regulated expression of TfR are well characterized, the mechanism by which the degradation of TfR is regulated is largely unknown. We show that an excess of iron enhances both TfR's ubiquitylation and degradation in lysosomes. Probably, the up-regulated expression of ferritin, an endogenous iron-chelating molecule, attenuated the iron-induced degradation of TfR. Exogenously introduced lysine-less TfR, compared to the wild-type one, showed resistance to the iron-induced ubiquitylation and degradation, when endogenous TfR, which most certainly heterodimerizes with exogenous ones, was depleted with siRNA. These data suggest that the iron-induced ubiquitylation and degradation of TfR along with MVB pathway physiologically plays an important role in iron homeostasis.
authors.affiliation: Division of Pharmaceutical Cell Biology, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Tachiyama
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ishikawa
authors.forename: Masaki
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Keiichi I
authors.initials: KI
authors.lastname: Nakayama
authors.forename: Tamotsu
authors.initials: T
authors.lastname: Yoshimori
authors.forename: Sadaki
authors.initials: S
authors.lastname: Yokota
authors.forename: Masaru
authors.initials: M
authors.lastname: Himeno
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Hideaki
authors.initials: H
authors.lastname: Fujita
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism*; D057146:Multivesicular Bodies / Q000502:physiology*; D020543:Proteome; D011990:Receptors, Transferrin / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism* / Q000502:physiology; D057149:Ubiquitinated Proteins / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D020543:Proteome; D011990:Receptors, Transferrin; D025801:Ubiquitin; D057149:Ubiquitinated Proteins; D007501:Iron; D000251:Adenosine Triphosphatases; D000074183:ATPases Associated with Diverse Cellular Activities; C490304:VPS4B protein, human